Throughout this application various references are referred to within parenthesis. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the sequence listing and the claims.
One of the important early events in the development of the mammalian central nervous system is the establishment of regional diversity along the neural tube under the influence of signals from the underlying mesoderm (Mangold 1933; Spemann 1938; Placzek et al. 1990). The caudal portion of the neural tube gives rise to the spinal cord while the rostral part develops into the brain. Morphologic studies have identified the initial subdivision of the developing brain into three vesicles, the forebrain, midbrain and hindbrain. The forebrain and hindbrain subsequently each subdivide, resulting in the five major regions of the brain. The most rostral region, the telencephalon, gives rise to the structures of the cerebral hemispheres which include the cerebral cortex and basal ganglia (Kandel et al. 1991). This subdivision of the developing brain is apparent initially as changes in the shape of the neuroepithelium, and is established prior to differentiation of the progenitor cells into neurons and glia (McKay 1989).
Our understanding of the molecular events which establish the regional subdivision of the brain during mammalian development have been aided by several approaches. Because development depends on the expression of genes in distinct spatial and temporal patterns, one approach has been the study of transcription factors which control gene expression in a cell or tissue-specific fashion. Another approach is the identification of mammalian homologs of Drosophila genes which have been established to play crucial roles in insect development (Kessel and Gruss 1990). For example, homeobox gene complexes in Drosophila and mammals are strikingly similar in structural organization and expression pattern along the A-P axis of the organism (Duboule and Dolle 1989; Graham et al. 1989). While recent findings of restricted expression in the developing brain of several homeodomain and one zinc finger proteins have provided insight into the development of the hindbrain (Murphy et al. 1989; Wilkinson et al. 1989; Wilkinson et al. 1989; Hunt et al. 1991). The molecular basis of forebrain development remains poorly understood.
We have recently described a novel family of transcriptional activators, the HNF-3 family, whose members function to stimulate expression of a group of liver-specific genes. The expression of these factors in the mature animal is limited to tissues which derive from the gut endoderm such as the liver, lung and intestine (Lai et al. 1991). These findings suggested that HNF-3 family members might play a significant role in the development of these tissues. This hypothesis was supported when we learned that HNF-3 proteins were highly homologous to a Drosophila protein, fork head, which had been shown to be critical to normal fly development and to be expressed in the cells which were to form the insect gut structures (Weigel et al. 1989; Weigel and Jackle 1990). In this paper we described the discovery of a new member of the HNF-3/fork head family of transcription factors which is unique in that its expression is restricted to the telencephalon of the developing rat brain. Expression is readily detectable by embryonic day 10 in the area of the neural tube which gives rise to the telencephalic vesicles suggesting a critical role for this factor in the development of this region of the forebrain.